Project Summary All populations are genetically variable, and humans, as well as the populations of somatic cells in their bodies, are no exception. Genetic variation explains much of phenotype variation and partially determines the risk of common and rare disease. Analysis of the functional effects of allelic variants opens a unique perspective on molecular function in the broad organismal context. Study of genetic variation provides understanding of the actions of evolution over short timescales and helps detect footprints of natural selection that point to uncharacterized functional elements of the genome. The explosion of sequencing datasets in combination with new computational and statistical techniques, propel genetic variation research. Our lab plans to be at the forefront of this endeavor. Our broad research program will analyze genetic variation from multiple angles. We will study mutagenesis as the origin of genetic variation, and use statistical analysis—in the context of known DNA replication and repair biology—to infer mutagenic mechanisms. We will develop computational methods to analyze and predict the effect of human allelic variants on molecular function. We will also study the evolutionary forces governing the fate of alleles in populations, in order to better understand the persistence of deleterious variation. Additionally, we will examine the principles of the relationship between genotype and phenotype, including both polygenic inheritance and the partial penetrance of rare disease variants. These topics—the origins, persistence, and effects of variants—are intertwined, and their integrated understanding is critical to the progress of human medical genetics and cancer genomics.